# OPHN1 translation and AMPA receptor plasticity during incubation of craving

> **NIH NIH F32** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $66,390

## Abstract

Project Summary
 A major problem for individuals suffering from addiction is the persistent vulnerability to relapse, even
after long periods of abstinence. In the `incubation of cocaine craving' model of relapse, rats self-administer
cocaine using an extended access procedure, and then experience a prolonged abstinence period. During
abstinence, rats exhibit a progressive intensification (incubation) of cue-induced cocaine craving. We have
shown that Ca2+-permeable AMPA receptors (CP-AMPAR), comprised exclusively of the GluA1 subunit,
accumulate in the nucleus accumbens core (NAcc) during abstinence and thereafter are required for the
expression of incubated cue-induced craving. Thus, understanding the mechanisms regulating CP-AMPAR
maintenance and removal may yield novel therapeutic targets for reducing craving and prolonging abstinence.
Work from our lab has shown that CP-AMPAR mediated currents in the NAcc require active protein translation,
as they are blocked by general protein translation inhibitors. Also, treatment with a general protein translation
inhibitor just before the cue-induced craving test reduces incubated seeking. However, little is known about the
specifics of this critical protein translation. Under some conditions, inhibition of general protein translation
actually increases the translation of a subset of mRNA with 5' upstream open reading frames, such as
Oligophrenin-1 (OPHN1). In the hippocampus, OPHN1 is necessary for eIF2α-mediated mGluR-LTD and the
removal of synaptic AMPARs. In the VTA, this pathway plays a role in bidirectional CP-AMPAR plasticity in
response to i.p. cocaine exposure. Thus, in our NAcc studies, treatment with protein translation inhibitors may
have increased translation of OPHN1, mimicking mGluR-LTD and removing synaptic CP-AMPARs. My
hypothesis is that, following cocaine self-administration and prolonged abstinence, OPHN1 translation is low in
the NAcc, permitting the accumulation and maintenance of CP-AMPARs. In addition, in incubated rats during
the seeking test, OPHN1 translation is reduced due to eIF2α-dephosphorylation, enabling CP-AMPARs to stay
in synapses during the test and mediate incubated seeking. Aim 1 will determine if OPHN1 translation is
dysregulated in incubated rats using viral Translating Ribosome Affinity Purification (vTRAP) coupled with
qRT-PCR to quantify Ophn1, Gria1 and Gria2 mRNA during incubation of cocaine craving. Changes in mRNA
will be compared to changes in newly translated proteins using puromycin-labeling of nascent proteins and
immunoblotting. I will also use several techniques to localize the critical translation. Aim 2 will determine the
role of OPHN1 in the expression of incubated seeking. Here I will use a similar vTRAP approach to
examine actively translated mRNAs before and after a seeking test in incubated rats. Also, I will experimentally
knockdown OPHN1 to test if it is necessary for mGlu1-LTD-mediated removal of CP-AMPARs and
normalization of incubated se...

## Key facts

- **NIH application ID:** 10129192
- **Project number:** 5F32DA050457-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Alexander Borg Kawa
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2020-03-02 → 2022-03-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129192

## Citation

> US National Institutes of Health, RePORTER application 10129192, OPHN1 translation and AMPA receptor plasticity during incubation of craving (5F32DA050457-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129192. Licensed CC0.

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